Role of p90RSK in regulating the Crabtree effect: implications for cancer

Abstract

High glucose inhibits mitochondrial respiration, known as the “Crabtree effect”, in cancer cells and possibly other cell types. The upstream pathways regulating this phenomenon are poorly understood. In diabetes, where glucose levels are elevated, the p90 ribosomal S6 kinase (p90RSK) has received much attention as a potential upstream mediator of the effects of high glucose. Evidence is also emerging that p90RSK may play a role in cancer cell signaling, although the role of p90RSK in regulating cancer cell metabolism is unclear. Herein we provide an overview of the Crabtree effect and its relationship to mitochondrial metabolism. Furthermore, preliminary data are presented suggesting a role for p90RSK and its upstream components, the ERK family of mitogen-activated protein kinases (MAPKs), in the Crabtree effect.

Dihydroartemisinin inhibits the Raf/ERK/MEK and PI3K/AKT pathways in glioma cells

“…The Raf/MEK/ERK pathway is one of the most common oncogenic pathways and is critical in driving cell proliferation, survival and preventing apoptosis. Upon activation by growth factors, serum, polypeptide hormones, neurotransmitters or chemokines, activated ERK phosphorylates and regulates multiple cytoplasmic signaling proteins and transcription factors (4). These events result in gene expression changes and alterations in cell survival, division and metabolism.…”

Cancer as a Metabolic Disease: Implications for Novel Therapeutics

“…The Crabtree effect involves a glucoseinduced suppression of respiration leading to lactate production whether or not mitochondria are damaged (96,120,125,126). The Crabtree effect differs from the Warburg effect, which involves lactate production arising from insufficient respiration.…”

MYC and Mitochondrial Biogenesis

“…Induction of endogenous MYC during cell-cycle entry is associated with a twofold increase in glucose oxidation, whereas inducible overexpression of MYC has been reported to inhibit glucose oxidation (Wise et al 2008;Morrish et al 2009;Fan et al 2010; but see Murphy et al 2013). This may reflect suppression of mitochondrial glucose metabolism under conditions of high glucose availability, akin to the Crabtree effect (Redman et al 2013), or low pyruvate availability due to substrate channeling.…”